The invention pertains to novel arylalkylbenzofuran derivatives having drug and bio-affecting properties, to their preparation, to pharmaceutical formulations containing them and to methods of using them. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. In mammals, melatonin levels show a cyclical, circadian pattern, with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology. 
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [125I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In the mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures.
Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific [125I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting that melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487 published on Apr. 14, 1994.
Melatonin binding sites have been found in diverse tissues of the body, i.e., in the retina, superchiasmatic nucleus, spleen, etc. This means that melatonin exerts multiple physiological effects and is not highly selective. The potential for side effects with melatonin use is large. Melatonin agonists should be more selective than melatonin and have fewer side effects. Suitable melatonin agonists could overcome melatonin""s drawbacks, resulting in products having more predictable and, possibly, sustained activity.
Melatonin agonists should be particularly useful for the treatment of chronobiological disorders. They would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, periondontitis, immune disorders, neuroendocrine disorders, and a variety of sleep disorders.
Aside from simple indole derivatives of melatonin itself, various amide structures have been prepared and their use as melatonin ligands disclosed. In general these amide structures can be represented as: 
wherein Z is an aryl or heteroaryl system attached by a two carbon chain to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application No. EP 527 687 A disclose, as melatonin ligands, ethylamines having cyclic substituents: 
wherein Arxe2x80x2 is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R1 is, inter alia, an alkyl or cycloalkyl group; and R2 is hydrogen or lower alkyl.
Matsuda, et al. in International Patent Application No. WO 95/22521 disclose 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as N-methyl-D-aspartate (NMDA) receptor antagonists, wherein R1 represents, inter alia, a C1-C5 linear saturated aliphatic, a C1-C5 linear unsaturated aliphatic, a branched aliphatic, or a phenyl group which may be substituted with one to three substituents selected independently from the group consisting of halogen, C1-C4 alkyl, nitro, amino, hydroxy, and C1-C4 alkoxy as shown below: 
The 1,2-diarylcyclopropane derivatives disclosed in NE 6701256 have CNS stimulant properties: 
wherein Ar1 and Ar2 are independently and optionally substituted phenyl; R1 is inter alia hydrogen, lower alkyl or acyl; R2 is inter alia alkyl, cycloalkyl or aralkyl.
Keavy et al. in U.S. Pat. No. 5,753,709 issued on May 19, 1998, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure: 
wherein X represents halogen, hydrogen, cyano, aryl, C1-4 alkyl or OR5 wherein, inter alia, R5 is hydrogen, C1-20 alkyl or C4-20 alkylcycloalkyl; Y is hydrogen or halogen; R is hydrogen, halogen or C1-4 alkyl; R1 is hydrogen, C1-4 alkyl or benzyl; and R2 is C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-4 alkoxyalkyl, C1-4 trifluoromethylalkyl or C2-8 alkylthioalkyl.
Catt et al. in U.S. Pat. No. 5,856,529 issued on Jan. 5, 1999, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure: 
wherein Q1 and Q2 represent hydrogen or halogen; X is CH2, CH or oxygen; Y is CR3, C3R4 or (CH2)n whereby n is 1 to 4; Z is CH2, CH or oxygen,; R is hydrogen, halogen or C1-4 alkyl; m is 1 or 2; R2 is hydrogen or C1-4 alkyl; and R1 is C1-6 alkyl, C3-6 cycloalkyl, C1-3 haloalkyl, C1-6 alkylamino, C2-6 alkenyl, C1-4 alkoxy(C1-4)alkyl, C1-4 alkylthio(C1-4)alkyl or C1-4 trifluoromethylalkyl.
Takaki et al. in U.S. Pat. No. 6,211,225 issued on Apr. 3, 2001, and assigned to the assignee of the present invention, discloses melatonergic agents of the following structure: 
wherein the wavy bond xcx9cxcx9c represents the racemate, the (R)-enantiomer or the (S)-enantiomer; R1 and R2 each are independently hydrogen or halogen; W is CR5, CR5R6 or (CH2)n with n being 1 to 2; Z is CH2, CH or oxygen; R3 is hydrogen or C1-4 alkyl; R4 is C1-6 alkyl, C3-6 cycloalkyl, C1-3 haloalkyl, C1-6 alkylamino, C2-6 alkenyl, C1-4 alkoxy(C1-4)alkyl, C1-4 alkylthio(C1-4)alkyl or C1-4 trifluoromethylalkyl; R5 and R6 are each independently hydrogen or C1-4 alkyl.
The foregoing disclosures do not teach or suggest the novel melatonergic benzofuran and dihydrobenzofuran derivatives of the present invention. The novel compounds of the present invention display melatonergic agonist activity.
This invention provides a novel series of compounds of Formula I: 
wherein R1, R2, R3, R4, R5, Y, W, m, and n are as defined below, including hydrates and solvates thereof which bind to human melatonergic receptors and, as thus, are useful as melatonergic agents in the treatment of sleep disorders, seasonal depression, shifts in circadian cycles, melancholia, stress, appetite regulation, benign prostatic hyperplasia, periodontitis, and related conditions.
The present invention provides a novel series of compounds of Formula I and hydrates and solvates thereof: 
wherein
the dashed line represents a single or double bond;
R1 and R2 are each independently hydrogen or halogen;
R3 is hydrogen or C1-4 alkyl;
R4 is C1-4 alkyl, C3-6 cycloalkyl, C1-3 haloalkyl, C2-6 alkenyl, C1-4 alkoxy, C1-2 trifluoromethylalkyl, or C1-4 alkylamino;
R5 is hydrogen, halogen, C1-4 alkyl, or C1-4 alkoxy;
Y is hydrogen or halogen;
W is ethylene or a 1,2 disubstituted cyclopropyl group;
m is 1 or 2; and
n is 1 to 9.
The present invention also provides a method of treating sleep disorders and related conditions by administering a therapeutically effective amount of a compound of Formula I or a solvate or hydrate thereof.
R1 and R2 are each independently hydrogen or halogen (i.e., bromine, chlorine, iodine or fluorine). It is most preferred that R1 is hydrogen and R2 is hydrogen.
R3 is hydrogen or C1-4 alkyl with hydrogen being most preferred.
R4 may be C1-4 alkyl, C3-6 cycloalkyl, C1-3 haloalkyl, C2-6 alkenyl, C1-4 alkoxy, C1-2 trifluoromethylalkyl, or C1-4 alkylamino. Preferably, R4 is C1-4 alkyl or C3-6 cycloalkyl with C1-4 alkyl being most preferred.
R5 is hydrogen, halogen, C1-4 alkyl, or C1-4 alkoxy. Preferably, R5 is hydrogen or halogen with hydrogen being most preferred.
X is ethylene or a divalent cyclopropyl group.
m is 1 or 2 with 1 being most preferred.
n is 1 to 9 with 1 to 4 being preferred, 2 to 4 being more preferred, and 3 to 4 being most preferred.
xe2x80x9cAlkylxe2x80x9d means a monovalent straight or branched chain group of the formula CxH2x+1, with x being the number of carbon atoms.
xe2x80x9cAlkenylxe2x80x9d means a straight or branched hydrocarbon radical containing a carbon-carbon double bond.
xe2x80x9cCycloalkylxe2x80x9d groups are monovalent cyclic moieties containing at least 3 carbon atoms and conforming to the formula CxH2xxe2x88x921, with x being the number of carbon atoms present. The cyclopropyl group is a preferred cycloalkyl moiety.
xe2x80x9cHaloalkylxe2x80x9d includes straight and branched chain hydrocarbon radicals bearing from 1 to 3 halogen moieties. xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, bromine, or iodine. Preferred halogens in haloalkyl moieties of R4 are fluorine and chlorine.
The compounds of Formula I encompass all pharmaceutically acceptable solvates, particularly hydrates, thereof. The present invention also encompasses diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds of Formula I. Separation of individual isomers or selective synthesis of the individual isomers is accomplished by application of various methods known to those of skill in the art.
When W is ethylene, the compounds of the present invention are represented by Formula II: 
wherein R1, R2, R3, R4, R5, m, and n are as defined above. Preferably, R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, R4 is C1-3 alkyl, R5 is hydrogen, m is 1, and n is 1 to 4.
The compounds of Formula II may be prepared using the processes depicted in the following Reaction Schemes 1 to 3. Reaction Scheme 1 illustrates a method of making the compounds of Formula II that contain chirality. Reaction Scheme 2 illustrates a method of making the compounds of Formula II that do not have chiral centers. Reaction Scheme 3 illustrates a method of making the compounds of Formula II that have substitution on the arylalkyl substituent of the benzofuran. Reaction Scheme 4 illustrates a method of making the compounds of Formula II having varying alkyl chain lengths of the arylalkyl substituent. 
Some preferred compounds of Formula II include: N-[3-[2-(4-phenylbutyl)-2,3-dihydrobenzofuran-4-yl]-propyl]acetamide; N-[3-[2-(4-phenylbutyl)-2,3-dihydrobenzofuran-4-yl]-propyl]propionamide; N-[3-[2-(4-phenylbutyl)-2,3-dihydrobenzofuran-4-yl]-propyl]butyramide; N-[3-[2-(4-phenylbutyl)-2,3-dihydrobenzofuran-4-yl]propyl]-2-methylpropionamide; N-[3-[2-(4-phenylbutyl)-2,3-dihydrobenzofuran-4-yl]propyl]-cyclopropanecarboxamide; N-[3-[2-(4-phenylbutyl)benzofuran-4-yl]propyl]propionamide; and N-[3-[2-(4-phenylbutyl)benzofuran-4-yl]propyl]-2-methylpropionamide.
As shown in Reaction Scheme 1, the phenolic moiety of ethyl 3-hydroxy-2-allylbenzoate 2 was protected as the MOM ether by treatment with chloromethylmethyl ether. The terminal olefin was then converted to the aldehyde by the action of osmium tetroxide and sodium periodate. Addition of allyl Grignard and lactonization of the intermediate alcohol produced lactone 5. Reduction of the lactone with DIBAL followed by a Horner-Emmons addition produced the cinnamate 7. The MOM ether was cleaved with methanolic HCl and an intramolecular Mitsunoble reaction afforded the cyclic ether 9. The ester was transesterified with methanolic HCl, the terminal olefin was hydroborated, and the resulting alcohol was oxidized under Swern conditions generating aldehyde 12. Wittig condensation followed by reduction of the olefin produced intermediate 14. The ester was converted to the carboxamide followed by DIBAL mediated reduction to give amine 17. The amine was then acylated with a variety of acylating agents to give dihydrobenzofuran compounds of structure 1.
Likewise, analogous benzofuran compounds were also prepared from intermediate 2 as illustrated in Reaction Scheme 2. Oxidation of 2 with m-CPBA generated the cyclic intermediate 18 which was acylated with acetic anhydride and then oxidized with DDQ to produce aldehyde 20. Wittig olefination followed by hydrogenation afforded benzofuran 22. Reduction of the ester with LAH followed by Swern oxidation produced aldehyde 24 which was homolygated via another Wittig reaction to generate cinnamylnitrile 25. Reduction of this compound with cobalt chloride and sodium borohydride followed by acylation afforded compounds of structure 27.
In Reaction Scheme 3, intermediate 20 was converted to intermediates 29a and 29b by successive Wittig reactions. Intermediate 35 was then prepared via the same sequence as that of conversion of 21 to 27.
In Reaction Scheme 4, starting material 2 was protected as the benzyl ether. The ester was then homolygated to cinnamonitrile 39 as described above and the olefin reduced to generate intermediate 40. Elaboration of the allyl group began with conversion to the aldehyde followed by Grignard addition; the resulting alcohols were oxidized to ketones. Debenzylation and cyclization created intermediates 44a and 44b. Transformation of the nitrile to amide 46 was as described previously.
In Reaction Scheme 5, intermediate 27 is chlorinated with N-chlorosuccinimide to provide compound 47, also referred to as Example 29.
When W is cyclopropyl, the compounds of the present invention are represented by Formula III: 
wherein R1, R2, R3, R4, R5, m, and n are as defined above. Preferably, R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, R4 is C1-3 alkyl, R5 is hydrogen, m is 1, and n is 1 to 4.
The compounds of Formula III may be prepared as depicted in the following Reaction Schemes 1A and 2A. Reaction Scheme 1A illustrates a method of making the benzofuran compounds of Formula II. Reaction 2A illustrates a method of making the dihydrobenzofuran compounds of Formula III. 
In Reaction Scheme 1A, intermediate 20 was converted to intermediate 4A by tandem Wittig reactions. Ester 4A was then converted to cinnamates 8 in a manner analogous to the conversion of intermediates 21 to 25. Cinnamates 8 were cyclopropanated by the action of palladium and diazomethane. The conversion of esters 9 to compounds 1A and 1B were analogous to the conversion of intermediate 14 to compound 1.
Scheme 2A, intermediate 5 was elaborated to intermediate 5Axe2x80x2 by the sequence of hydroboration, Swern oxidation, and Wittig olefination. After hydrogenation of the olefin, intermediate 6Axe2x80x2 was converted to intermediate 10Axe2x80x2 by same sequence as that of intermediates 5 to 9. The ester was converted to the chiral sultam and the olefin cycloprapanated with palladium and diazomethane to afford intermediate 13Axe2x80x2. The sultam was reduced to the alcohol with LAH and the alcohol transformed to the amine by Swern oxidation, oxime formation, and reduction of the oxime. Amide 1Axe2x80x2 was then prepared by acylation.
Some preferred compounds of Formula III include: N-({(1R,2R)-2-[2-(4-phenylbutyl)benzo[b]furan-4-yl]cyclopropyl}methyl)acetamide; (xe2x88x92)N-({(1R,2R)-2-[2-(4-phenylbutyl)benzo[b]furan-4-yl]cyclopropyl}methyl)acetamide; N-({(1R,2R)-2-[2-(4-phenylbutyl)benzo[b]furan-4-yl]-cyclopropyl}methyl)propanamide; N-({2-[(2R)-2-(4-phenylbutyl)(2,3-dihydrobenzo[b]furan-4-yl)](1R,2R)cyclopropyl}methyl)acetamide; N-({2-[(2R)-2-(4-phenylbutyl)(2,3-dihydrobenzo[b]furan-4-yl)]-(1R,2R)cyclopropyl}methyl)propanamide; N-({2-[(2R)-2-(4-phenylbutyl)(2,3-dihydrobenzo[b]furan-4-yl)]-(1R,2R)cyclopropyl}methyl)butanamide; and N-({2-[(2R)-2-(4-phenylbutyl)(2,3-dihydrobenzo[b]furan-4-yl)](1R,2R)cyclopropyl}methyl)cyclopropylcarboxamide.
The compounds of the present invention are melatonergic agents. They have been found to bind to human melatonergic receptors expressed in a stable cell line with good affinity. Further, the compounds are agonists as determined by their ability, like melatonin, to block the forskolin-stimulated accumulation of cAMP in certain cells. Due to these properties, the compounds and compositions of the present invention should be useful as sedatives, chronobiotic agents, anxiolytics, antipsychotics, analgesics, and the like. Specifically, these agents should find use in the treatment of stress, sleep disorders, seasonal depression, appetite regulation, shifts in circadian cycles, melancholia, benign prostate hyperplasia, inflammatory articular disease, periodontitis, and related conditions.
Melatonergic Receptor Binding Activity
1. Reagents:
(a) TME=50 mM Tris buffer containing 12.5 mM MgCl2, and 2 mM EDTA, pH 7.4 at 37xc2x0 C., with concentrated HCl.
(b) Wash buffer: 20 mM Tris base containing 2 mM MgCl2, pH 7.4 at room temperature.
(c) 10xe2x88x924 M melatonin (10xe2x88x925 M final concentration).
(d) 2-[125I]-iodomelatonin, 0.1 M final concentration.
2. Membrane Homogenates: The melatonin ML1xcex1 receptor cDNA was subcloned into pcDNA3 and introduced into NIH-3T3 cells using Lipofectamine. Transformed NIH-3T3 cells resistant to geneticin (G-418) were isolated, and single colonies expressing high levels of 2-[125I]-iodomelatonin binding were isolated. Cells are maintained in DMEM supplemented with 10% calf serum and G-418 (0.5 g/liter). Cells are grown to confluency in T-175 flasks, scraped using Hank""s balanced salt solution, and frozen at xe2x88x9280xc2x0 C. For preparing membrane homogenates, pellets are thawed on ice, and re-suspended in TME buffer in the presence of 10 xcexcg/ml aprotinin and leupeptin, and 100 xcexcM phenylmethylsulfonylfluoride. The cells were then homogenized using a dounce homogenizer, and centrifuged. The resulting pellet was re-suspended with dounce homogenizer in TME (supplemented with the above protease inhibitors) and frozen. On the day of assay, a small aliquot was thawed on ice and re-suspended in the ice cold TME (1:50-1:100 v/v) and held on ice until assayed.
3. Incubation: 37xc2x0 C. for 1 hour. Reaction is terminated by filtration. Filters were washed 3 times.
4. References: Reppert, et al., Neuron, 13, p. 1177-1185 (1994).
Based on biological tests, the following Formula I compounds are preferred. All have binding affinities for the human melatonin receptor with IC50 values of 600 nM or less.
The compounds of the present invention have affinity for receptors of the endogenous pineal hormone, melatonin, as determined in a receptor binding assays described above in Tables I to V for the ML1a and ML1b (human) receptors. Melatonin is involved in the regulation of a variety of biological rhythms and exerts its biological effects via interaction with specific receptors. There is evidence that administration of melatonin agonists are of clinical utility in the treatment of various conditions regulated by melatonin activity. Such conditions include depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, some disorders associated with reproduction, cancer benign prostatic hyperplasia, immune disorders and neuroendocrine disorders.
For therapeutic use, the pharmacologically active compounds of Formula I will normally be administered as a pharmaceutical composition comprising as the (or an) essential active ingredient at least one such compound in association with a solid or liquid pharmaceutically acceptable carrier and, optionally with pharmaceutically acceptable adjuvants and excipients employing standard conventional techniques.
The pharmaceutical compositions include suitable dosage forms for oral, parenteral (including subcutaneous, intramuscular, intradermal and intravenous) transdermal, bronchial or nasal administration. Thus, if a solid carrier is used, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge. The solid carrier may contain conventional excipients such as binding agents, fillers, tableting lubricants, disintegrants, wetting agents and the like. The tablet may, if desired, be film coated by conventional techniques. If a liquid carrier is employed, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, sterile vehicle for injection, an aqueous or non-aqueous liquid suspension, or may be a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicle (including edible oils), preservatives, as well as flavoring and/or coloring agents. For parenteral administration, a vehicle normally will comprise sterile water, at least in large part, although saline solutions, glucose solutions and the like may be utilized. Injectable suspensions also may be used, in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like also may be added to the parenteral dosage forms. Particularly useful is the administration of a compound of Formula I in oral dosage formulations. The pharmaceutical compositions are prepared by conventional techniques appropriate to the desired preparation containing appropriate amounts of the active ingredient, that is, the compound of Formula I according to the invention. See for example, Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.
In making pharmaceutical compositions containing compounds of the present invention, the active ingredient(s) will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or a liquid medium), ointments containing for example up to 1:0% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl- and propyl-hydroxybenzoates, talc, magnesium stearate and mineral oil. The formulations can additionally include lubricating agents, wetting agents emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient.
The dosage of the compounds of Formula I to achieve a therapeutic effect will depend not only on such factors as the age, weight and sex of the patient, and mode of administration, but also on the degree of melatonergic activity desired and the potency of the particular compound being utilized for the particular disorder or condition concerned. It is also contemplated that the treatment and dosage of the particular compound may be administered in unit dosage form and that the unit dosage form would be adjusted accordingly by one skilled in the art to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the physician, and may be varied by titration of the dosage to the particular circumstances of this invention to produce the desired therapeutic effect.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.1 to 100 mg, more usually 1 to 10 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
These active compounds are effective over a wide dosage range. For example, dosages per day will normally fall within the range of about 0.1 to 500 mg. In the treatment of adult humans, the range of about 0.1 to 10 mg/day, in single or divided doses, is preferred. Generally, the compounds of the invention may be used in treating sleep and related disorders in a manner similar to that used in treating sleep and related disorders in a manner similar to that used for melatonin.
However, it will be understood that the amount of the compound actually administered will be determined by a physician, in light of the relevant circumstances including the condition to be treated, the choice of compound to be administered, the chosen route of administration, the age, weight and response of the individual patient, and the severity of the patient""s symptoms.